Antiviral activity of amides and carboxamides of quinolizidine alkaloid (−)-cytisine against human influenza virus A (H1N1) and parainfluenza virus type 3

Abstract

Novel derivatives of quinolizidine alkaloid (−)-cytisine were synthesised. ADME properties, cytotoxicity against HEK293 cells and activity against viruses of influenza A/California/07/09(H1N1)pdm09 virus (IAV) and human parainfluenza virus type 3 (HPIV3) were evaluated. It was shown, that 9-carboxamides of methylcytisine (with phenyl and allyl urea’s fragments) are most active compounds against IAV probably due to predicted in silico peculiarity of their interactions with the 4R7B active site of IAV neuraminidase. Indexes of selectivity (SI) calculated as ratio of CC₅₀/IC₅₀ of these ureas are 47 and 59 correspondingly. It was also found, that derivatives obtained from allyl isocyanate and (−)-cytisine or 9,11-dibromocytisine are able to inhibit a reproduction of HPIV3 with SI = 58 and 95. Moreover, last compound - (1 R,5R)-N-allyl-9,11-dibromo-8-oxo-1,5,6,8-tetrahydro-2H-1,5-methanopyrido[1,2-a][1,5]diazocine-3(4H)-carboxamide with two bromine atom in 2-pyridone core of starting (−)-cytisine molecule, demonstrated high activity against HPIV3 (SI = 95) and moderate activity against IAV (SI = 16).

Graphical Abstract

Keywords:

• (−)-Cytisine
• ureas
• influenza virus
• parainfluenza virus
• ADME
• HEK293
• molecular docking

Disclosure statement

The authors reported no potential conflict of interest.

Additional information

Funding

All experiments were carried out using the equipment of Collective Use Service Centre ‘Chemistry’ of Ufa Institute of Chemistry UFRС RAS.